Nutrient availability is central for T-cell functions and immune responses. Here we report that CD8⁺ T-cell activation and anti-tumour responses are strongly potentiated by the non-essential amino acid Asn. Increased Asn levels enhance CD8⁺ T-cell activation and effector functions against tumour cells in vitro and in vivo. Conversely, restriction of dietary Asn, ASNase administration or inhibition of the Asn transporter SLC1A5 impairs the activity and responses of CD8⁺ T cells. Mechanistically, Asn does not directly alter cellular metabolic fluxes; it instead binds the SRC-family protein tyrosine kinase LCK and orchestrates LCK phosphorylation at Tyr 394 and 505, thereby leading to enhanced LCK activity and T-cell-receptor signalling. Thus, our findings reveal a critical and metabolism-independent role for Asn in the direct modulation of the adaptive immune response by controlling T-cell activation and efficacy, and further uncover that LCK is a natural Asn sensor signalling Asn sufficiency to T-cell functions.

营养物质的可用性对于 T 细胞功能和免疫反应至关重要。在这里，我们报告了非必需氨基酸 Asn 强烈增强了CD8 ^{+ T 细胞活化和抗肿瘤反应。}Asn 水平升高可在体外和体内增强 CD8 ^{+ T 细胞活化和针对肿瘤细胞的效应器功能。}相反，限制饮食 Asn、ASNase 给药或抑制 Asn 转运蛋白 SLC1A5 会削弱 CD8 ^{+的活性和反应}T细胞。从机制上讲，Asn 不会直接改变细胞代谢通量；相反，它结合 SRC 家族蛋白酪氨酸激酶 LCK 并协调 Tyr 394 和 505 处的 LCK 磷酸化，从而导致 LCK 活性和 T 细胞受体信号传导增强。因此，我们的研究结果揭示了 Asn 在通过控制 T 细胞活化和功效来直接调节适应性免疫反应中的关键且独立于代谢的作用，并进一步揭示 LCK 是一种天然的 Asn 传感器，可将 Asn 信号传递给 T 细胞功能.